Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone. The terms multiple myeloma and myeloma are used interchangeably.
Plasma cells produce antibodies, proteins that move through the bloodstream to help the body get rid of harmful substances. Each type of plasma cell responds to only one specific substance by making a large amount of one kind of antibody. These antibodies find and act against that one substance. Because the body has many types of plasma cells, it can respond to many substances. When cancer involves plasma cells, the body keeps producing more and more of these cells. The unneeded plasma cells—all abnormal and all exactly alike—are called myeloma cells. Myeloma cells tend to collect in the bone marrow and in the hard outer part of bones. Sometimes they collect in only one bone and form a single mass, or tumor, called a plasmacytoma. In most cases, however, the myeloma cells collect in many bones, often forming many tumors and causing other problems. When this happens, the disease is called multiple myeloma (MM).
Because people with MM have an abnormally large number of identical plasma cells, they also have too much of one type of antibody. The tumor, its products, and the host response to it result in a number of organ dysfunctions and symptoms of bone pain or fracture, renal failure, susceptibility to infection, anemia, hypercalcemia, and occasionally clotting abnormalities, neurologic symptoms, and vascular manifestations of hyperviscosity.
MM is the 2nd most commonly diagnosed hematologic malignancy in the Western World, with an annual incidence of ˜15,000 new cases in the U.S. alone, and is the 14th cause of death by cancer when considering all tumors. Unfortunately, MM is presently considered an incurable disease and the overall survival of MM patients has remained essentially unchanged at a median of 3-4 years, despite intense efforts over the last ˜3 decades to improve on the activity of cytotoxic chemotherapy-based therapies for this disease. Importantly, the median age of diagnosis of MM is <65 years old and >⅓ of MM patients are <55 years old at diagnosis. For this substantial proportion of relatively young MM patients, the diagnosis of MM signifies, even in the absence of other co-morbidities, a high probability that their overall survival will be significantly shorter than the average life-expectancy of age-matched non-MM patients.
Recently, there have been a series of important advances in the therapeutic management of MM, namely the documentation of anti-MM activity of two new classes of anti-cancer agents: thalidomide (and its immunomodulatory derivatives such as lenalidomide (Dimopoulos M et al. N. Engl. J. Med. 2007, 357, 2123-2132; Weber D M et al. N. Engl. J. Med. 2007, 357, 2133-2142)) and the proteasome inhibitors such as bortezomib (Richardson P G et al. N. Engl. J. Med. 2005, 352, 2487-2498). Although these classes of agents have been shown to be active in the setting of MM patients who were relapsed/refractory to conventional or high-dose cytotoxic chemotherapy-based regimens, a significant proportion of MM patients has de novo resistance to those novel agents, while initial responders (even those achieving durable complete remissions) can eventually relapse. Therefore the development of novel classes of anti-MM agents is urgently needed, in order to further improve the outcome of MM patients and, hopefully, to achieve high cure rates for this presently incurable neoplasia.
More information about MM can be found in the medical literature such as in the “Handbook Cancer. Principles & Practice of Oncology”, 7th ed. Philadelphia, Pa.: Lippincott Williams & Wilkins, 2005.
PM00104 is an alkaloid related to Jorumycin and Renieramycins, and also to safracin and saframycin compounds. Jorumycin is a natural compound isolated from the skin and from the mucus of the Pacific nudibranch Jorunna funebris (Fontana A., et al., Tetrahedron (2000), 56, 7305-8). In addition, the family of Renieramycins is disclosed as being isolated from sponges and tunicates (James M. F. et al. J. Am. Chem. Soc. (1982), 104, 265-269; Oku N., et al. Journal Natural Products (2003), 66, 1136-9). Safracin and saframycin compounds are disclosed in Manzanares I., et al. Curr. Med. Chem. Anti-Cancer Agents (2001), 1, 257-276, as well as in WO 00/18233 and WO 01/87894.
PM00104 has demonstrated a significant in vitro activity against solid and non-solid tumour cell lines as well as significant in vivo activity in several xenografted human cell lines in mice, such as breast and prostate cancer lines. Preliminary insights into the mechanism of action of PM00104 suggested cell cycle changes, DNA binding properties and transcriptional inhibition. For further details of PM00104 see WO 01/87894. This compound shows the following chemical structure:

Additionally, the reader is referred to WO 2007/052076 and WO 2008/135792, which are incorporated herein by specific reference, for pharmaceutical compositions and administration dosages and schedules of PM00104.
It is an object of the present invention to provide new and improved forms of treatment of MM by using PM00104.
It is another object of the present invention to provide new uses in cancer therapy for PM00104.